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Differential regulation of the Let-7 family of microRNAs in CD4+ T cells alters IL-10 expression

Abstract

MicroRNAs (miRNAs) are approximately 22-nt small RNAs that are important regulators of mRNA turnover and translation. Recent studies have shown the importance of the miRNA pathway in HIV-1 infection, particularly in maintaining latency. Our initial in vitro studies demonstrated that HIV-1-infected HUT78 cells expressed significantly higher IL-10 levels compared with uninfected cultures. IL-10 plays an important role in the dysregulated cytotoxic T cell response to HIV-1, and in silico algorithms suggested that let-7 miRNAs target IL10 mRNA. In a time course experiment, we demonstrated that let-7 miRNAs fall rapidly following HIV-1 infection in HUT78 cells with concomitant rises in IL-10. To show a direct link between let-7 and IL-10, forced overexpression of let-7 miRNAs resulted in significantly reduced IL-10 levels, whereas inhibition of the function of these miRNAs increased IL-10. To demonstrate the relevance of these results, we focused our attention on CD4(+) T cells from uninfected healthy controls, chronic HIV-1-infected patients, and long-term nonprogressors. We characterized miRNA changes in CD4(+) T cells from these three groups and demonstrated that let-7 miRNAs were highly expressed in CD4(+) T cells from healthy controls and let-7 miRNAs were significantly decreased in chronic HIV-1 infected compared with both healthy controls and long-term nonprogressors. We describe a novel mechanism whereby IL-10 levels can be potentially modulated by changes to let-7 miRNAs. In HIV-1 infection, the decrease in let-7 miRNAs may result in an increase in IL-10 from CD4(+) T cells and provide the virus with an important survival advantage by manipulating the host immune response.

Type Journal
Authors Swaminathan, S.; Suzuki, K.; Seddiki, N.; Kaplan, W.; Cowley, M. J.; Hood, C. L.; Clancy, J. L.; Murray, D. D.; Mendez, C.; Gelgor, L.; Anderson, B.; Roth, N.; Cooper, D. A.; Kelleher, A. D.:
Garvan Authors Dr Mark Cowley
Publisher Name J IMMUNOL
Published Date 2012-06-15 00:00:00
Published Volume 188
Published Issue 12
Published Pages 6238-46
URL http://www.ncbi.nlm.nih.gov/pubmed/22586040
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11421_11919/12 Swaminathan JImm_.pdf